Selected cell receptor genotypes differentially modulate the ABO blood group influence on Factor VIII levels in severe aortic stenosis.

BACKGROUND

Altered blood flow, which characterizes aortic stenosis (AS), influences von Willebrand factor (VWF) conformation and enhances ADAMTS13 cleavage, potentially influencing factor VIII (FVIII) clearance and plasma levels.

AIM: To investigate whether ABO blood group and genetic variants of cellular receptors involved in VWF/FVIII clearance may interact with AS in determining genotype-driven FVIII levels.

PATIENTS/

METHODS

FVIII:c levels were analyzed in patients with severe AS (SAS, n = 115), with coronary artery disease and without valvular heart disease (CAD, n = 300), and healthy subjects (HS, n = 172), clustered according to ABO and receptor genotypes. Variants with functional association with receptor mRNA and/or FVIII levels, localized in 5 receptors (LDLR, STAB2, SCARA5, ASGR2, CLEC4M) with different VWF/FVIII binding properties, were selected.

RESULTS

In SAS group, a significant interaction between ABO and receptor genotypes in modulating FVIII:c levels was observed with positive B values for lectins (ASGR2 and CLEC4M) and negative for LDLR and STAB2. The lectin variants, as well as their combinations, showed significantly lower FVIII levels in the non-O group with high glycan expression and potentially improved FVIII binding and increased clearance. Differently, the non-lectin LDLR and STAB2 variants, and their combinations, were associated with genotype-driven high FVIII levels, particularly in the O group. All these patterns were not observed in CAD or HS groups.

CONCLUSION

These observations suggest that differential interaction between genotypes of specific cellular receptors and ABO blood group may contribute to high/low FVIII:c levels in O/non-O blood group subjects, respectively, and to the large inter-individual variability of FVIII levels in SAS.